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The Dehydrogenase Hypothesis

  • Conor Woods
  • Jeremy W. Tomlinson
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 872)

Abstract

Circulating glucocorticoid (GC) levels are controlled by the Hypothalamo–Pituitary–Adrenal (HPA) axis, but within tissues, GC availability is controlled by the isoforms of 11β (Beta)-Hydroxysteroid Dehydrogenase 11β (Beta)-HSD that interconvert inactive cortisone and active cortisol. Two isoforms have been identified; in key metabolic target tissues (including liver and adipose), expression of 11β (Beta)-HSD1 predominates that in vivo converts cortisone to cortisol and thus amplifies local GC action. In contrast, in mineralocorticoid target tissues 11β (Beta)-HSD2 is the isoform that is most abundantly expressed. This inactivates cortisol to cortisone and offers protection for the mineralocorticoid receptor form occupation and activation by cortisol. Dysregulated 11β (Beta)-HSD1 activity has been implicated in many metabolic diseases such as obesity and diabetes and inhibition of 11β (Beta)-HSD1 represents a promising therapeutic target. Mutations within the gene encoding 11β (Beta)-HSD2 cause the Syndrome of Apparent Mineralocorticoid Excess and decreases in activity are linked to hypertension as well as impairment in placental function and neonatal growth. We will discuss the molecular biology and enzymology of 11β (Beta)-HSD and its role in normal physiology and discuss altered 11β (Beta)-HSD activity in pathological states and the potential for therapeutic targeting.

Keywords

11β (Beta)-HSD Endoplasmic reticulum (ER) Cortisol Cortisone H6PDH NADPH 

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Department of Diabetes and EndocrinologySt Vincent’s University HospitalDublinIreland
  2. 2.Oxford Centre for Diabetes, Endocrinology & MetabolismUniversity of Oxford, Radcliffe Department of MedicineOxfordUK

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